Project Summary Congenital heart disease (CHD) is the most common birth defect. Tremendous advances in surgical strategies and hospital care markedly increased survival rates such that a majority of CHD infants reach adulthood. CHD survivors often suffer poor neurological outcomes compared with their peers, which pose substantial burdens on patients and families. The urgent need for research aimed at identifying the cause(s) of altered brain maturation associated with long-term neurological deficits in CHD has recently been brought into clinical focus. Reduced cortical growth is a key signature of altered brain maturation in CHD but the cellular mechanisms underlying this process remain unknown. The primary goal of our proposal is to determine how CHD alters neuronal migration to the cortex during critical stages of brain development. To accomplish this, we will utilize a newly developed preclinical swine model of CHD as a platform for cell-dynamic studies. With this model, we were previously able to identify key sources of newborn cortical neurons and disruption to one of their migratory routes. Our novel preliminary data reveal numerous complex migratory paths of newborn neurons along a diverse host of substrates during perinatal cortical growth. We propose to test the hypothesis that reduced cerebral oxygenation in CHD disrupts neural precursor migration to the cortex in a substrate- dependent manner. Understanding the relationship between newborn neuronal migration along vulnerable and resistant substrates is a critical step in defining the molecular mechanisms and micro-environmental cues regulating immature cortical growth in CHD. The proposed investigation will provide key insights into potential targets for cell-based regenerative strategies to improve brain maturation and neurological outcomes in the growing CHD population.